rs121908441

Positions:

chr11-74457268-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM5BP6BS2

The NM_005472.5(KCNE3):c.296G>A(p.Arg99His) variant causes a missense change. The variant allele was found at a frequency of 0.0002 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R99C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

KCNE3
NM_005472.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:2

Conservation

PhyloP100: 5.17

Variant links:

Genes affected

KCNE3 (HGNC:6243): (potassium voltage-gated channel subfamily E regulatory subunit 3) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, isk-related subfamily. This member is a type I membrane protein, and a beta subunit that assembles with a potassium channel alpha-subunit to modulate the gating kinetics and enhance stability of the multimeric complex. This gene is prominently expressed in the kidney. A missense mutation in this gene is associated with hypokalemic periodic paralysis. [provided by RefSeq, Jul 2008]

KCNE3 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-74457269-G-A is described in Lovd as [Likely_pathogenic].

BP6

Variant 11-74457268-C-T is Benign according to our data. Variant chr11-74457268-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5542.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNE3	NM_005472.5 linkuse as main transcript	c.296G>A	p.Arg99His	missense_variant	3/3	ENST00000310128.9	NP_005463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
KCNE3	ENST00000310128.9 linkuse as main transcript	c.296G>A	p.Arg99His	missense_variant	3/3	1	NM_005472.5	ENSP00000310557	P1
KCNE3	ENST00000525550.1 linkuse as main transcript	c.296G>A	p.Arg99His	missense_variant	2/2	1		ENSP00000433633	P1
	ENST00000533008.1 linkuse as main transcript	n.155-26909C>T		intron_variant, non_coding_transcript_variant		3
KCNE3	ENST00000532569.5 linkuse as main transcript	c.296G>A	p.Arg99His	missense_variant	3/3	4		ENSP00000431739

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000956

AC:

AN:

250918

Hom.:

AF XY:

0.0000958

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.0000794

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000211

AC:

308

AN:

1461680

Hom.:

Cov.:

AF XY:

0.000204

AC XY:

148

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000327

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.0000563

Gnomad4 NFE exome

AF:

0.000244

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000184

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Brugada syndrome 6

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 99 of the KCNE3 protein (p.Arg99His). This variant is present in population databases (rs121908441, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of KCNE3-related conditions (PMID: 19122847, 19306396, 28855170, 29247119). ClinVar contains an entry for this variant (Variation ID: 5542). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change affects KCNE3 function (PMID: 19122847, 19306396). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2009	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jul 09, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2023	Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); Reported in association with torsades de pointes, cardiomyopathy, congestive heart failure and sudden unexplained death (Ohno et al., 2009; Wang et al., 2017; Lin et al., 2017); Functional studies showed increased current intensity when co-transfected with KCND3, though showed no alteration in current magnitude or kinetics when co-transfected with KCNQ1 (Delpon et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19122847, 30662450, 30821013, 23861362, 29247119, 28855170, 32600061, 19306396) -

Brugada syndrome

Benign:1

Likely benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

D;D;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

.;D;D

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.49

T;T;D

MetaSVM

Uncertain

0.76

MutationAssessor

Benign

1.8

L;L;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.7

N;N;N

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0040

D;D;D

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

D;D;.

Vest4

0.58

MVP

0.99

MPC

0.16

ClinPred

0.096

GERP RS

5.8

Varity_R

0.71

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over